Transdermal absorption of active substances from subcooled melts

ABSTRACT

A pharmaceutical product for the release of medicinal agents to the skin having absorption-increasing auxiliary agents is characterized in that the auxiliary material forms subcooled melts.

This application is a continuation of Ser. No. 09/436,717 filed Nov. 9,1999, now abandoned, which is a continuation of Ser. No. 08/860,961filed Nov. 7, 1997, now U.S. Pat. No. 6,264,980, which is a 371 ofPCT/EP95/05006 filed Dec. 18, 1995.

The present invention relates to the transdermal application ofmedicinal agents with the aid of inactive ingredients forming sub-cooledmelts. Applying pharmaceuticals transdermally undoubtedly is veryadvantageous, but the limited quantity of medicinal substance that canbe absorbed by the skin frequently is a disadvantage. With introducingthe therapy by means of transdermal application there have thereforebeen attempts to increase the pharmaceuticals' capability of penetratingthrough the skin. The development of penetration enhancers added todrugs for dermal application is regarded as one approach. Thesesubstances change subjacent skin structures, at least for a shortperiod; in unfavorable cases they may result in undesired side effects.These side effects are the less marked, the better the penetrationenhancers are tolerated physiologically.

A neat approach of increasing the absorption of medicinal agents throughthe skin is the manufacture of matrix systems. Owing to theconcentration gradient the dissolved portion of the active substancediffuses out of the system into the skin first. At the same time, theportion of active substance which is contained in the system insuspended form starts to dissolve. The dissolution rate of the activesubstance in the system is the factor determining the rate of activesubstance release. Experiments have shown that dodecanol promotespenetration and is physiologically acceptable. Since its melting pointamounts to about 24° C. dodecanol is solid at normal room temperature.The solid state makes it more difficult to deliver dodecanol out of amatrix. This deficiency restricts the use of dodecanol in polymericmatrices because the release rate of a substance from polymer matricesis the higher, easier it can diffuse, in as the matrix. This does notonly apply to dodecanol, but also to other penetration enhancers whichare solid at room temperature.

Accordingly it is the object of the present invention to improve therelease of auxiliary agents which are solid at room temperature from amatrix.

Most surprisingly, this object has been achieved according to thepresent invention by a pharmaceutical product as defined herein.Compounds forming subcooled melts are understood to mean those whosemelting point is above room temperature but which, after a meltingprocess, remain in the liquid state during cooling to room temperature.

The term drug is known to the skilled artisan. Ointments representinggels of plastic deformability as well as pastes which may becharacterized as ointments having a high solids content are suitable forthe application to the skin or mucous membranes (e.g. nose, eye).

A transdermal therapeutic system (TTS) is to be understood according toZaffaroni as “a medicinal substance-containing device or administrationform continuously releasing one or several medicinal agents at apredetermined rate over a predetermined period of time to a fixed placeof application” (quoted according to Heilmann, therapeutischeSysteme—Konzept und Realisation programmierter Arzneiverabreichung, 4thedition, Ferdinand Enke Verlag, Stuttgart 1984, page 26). In the presentcase the place of application is the skin.

The structure of transdermal systems is known to the skilled artisan.Patents describing the basic design include, for example, DE 3315272, DE3843239, U.S. Pat. No. 3,598,122.

When a transdermal therapeutic system is applied on the skin of apatient, the medicinal agent is to be released to take a topical orsystemic effect in the patient. Administration forms of this kind havealready been used in therapy. In most cases they have a layeredstructure; in the simplest case they consist of a backing layer, aself-adhesive active substance reservoir, and a removable protectivelayer to be removed prior to application. In the present case, anauxiliary agent must be introduced that increases the absorption ofmedicinal agents by the skin, is solid at room temperature, and formssubcooled melts, for example, dodecanol or levulic acid.

Substances are used as medicinal agents which—when applied on the skineither without or with an absorption filter—produce a local or systemiceffect.

Substances having a local action include, for example, antiperspirants,fungicides, bactericides, and bacteriostatics.

Substances having a systemic action include, for example, antibiotics,hormones, antipyretics, antidiabetic agents, coronary vasodilators,cardio-active glycosides, analgesics, spasmolytics, antihypertensives,psychotropic drugs, migraine analgesics, corticoids, contraceptives,antirheumatics, anticholinergics, sympathicolytics, sympathicomimetics,vasodilators, anticoagulants, and antiarrhythmics. This listing isincomplete.

The delivery of pilocarpine base and ephedrine base from polymermatrices can also be increased, provided that they are present insubcooled melts. Owing to their heat-sensitivity, however, it isimpossible to subject these medicinal substances to a melting process.

The present invention will be illustrated by the following Examples:

EXAMPLE 1

1,139 g of a 47.83%-wt. polyacrylate solution of a self-crosslinkedacrylate copolymer of 2-ethylhexyl acrylate, vinyl acetate, acrylicacid, (solvent: ethylacetate:heptane:isopropanol:toluene:acetylacetonate in the ratio of37:26:26:4:1), 100 g of levulic acid, 150 g of oleyl oleate, 100 g ofpolyvinylpyrrolidone, 150 g of ethanol, 200 g of ethyl acetate, and 100g of buprenorphine base are homogenized. The mixture is stirred forabout 2 hours; and dissolution of all solids is controlled visually. Theevaporation logs is controlled by reweighing, the possible solvent lossis replenished by ethyl acetate.

Subsequently, the mixture is applied on a transparent polyester film of420 mm in width in such a manner that the mass per unit area of the dryadhesive layer amounts to about 80 g per m². The polyester film renderedremovable by means of siliconization serves as protective layer.

The solvents are removed by drying with heated air which is guided overthe moist web. The heat treatment results in evaporation of thesolvents, but also in melting of the levulic acid. Afterwards theadhesive film is covered with a polyester film of 15μ. An area of 16 cm²is punched by means of suitable cutting tools, and the edges leftbetween the individual systems are removed. Examples 2 to 5 wereconducted in accordance with Example 1.

Column 1 indicates the number of the experiment, column 2 theconcentration of buprenorphine base, column 3 the quality and quantityof the acid used, column 4 the dissociation constant of the acids used,column 5 the plasticizer, column 6 the polymers used, and column 7 theabsorption rate under in-vitro-conditions. The relative amount ofbuprenorphine base diffusing through mice skin within 24 h, relative tothe amount per TTS, is given. The penetration results were obtainedusing mice skin clamped in a Franz-Cell. The composition of Examples 2-5are shown in Table 1.

The results of the in-vitro-penetration tests and the qualitative andquantitative compositions of buprenorphine-TTS according to Examples 1-5are represented in Table 1:

TABLE 1 Flux of buprenorphine base from TTSs having different acidsPenetration [%] buprenorphine base Buprenorphine pK_(a) relative to theamount of Example base Acid value Plasticizer Polymers medicinal agentin TTS 1 10% 10% glutaric acid 4.33* cetiol 10% dry polyacrylate 28.6monomethyl ester 70% 2 10% 15% octanoic acid 4.85 cetiol 10% drypolyacrylate 55% 5.9 PVP 10% 3 10% 10% levulic acid 4.4** cetiol 10% drypolyacrylate 60% 38.6 PVP 10% 4 10% 15% undecenoic 4.5 cetiol 10% drypolyacrylate 55% 7.7 acid DAB 10 PVP 10% 5 10% undecenoic 10% 4.5dodecanol 10% dry polyacrylate 27.3 *pK_(a) I of glutaric acid**determined by experiment Cetiol = oleyl oleate DAB 10 PVP =polyvinylpyrrolidone DAC

It is seen from column 4 that the dissociation constants of thecarboxylic acids used are quite similar. However, if the plasticizer,oleyl oleate, is used in a 10%-concentration each time, it can be seenfrom Examples 1 and 3 or 2 and 4 that only the carboxylic acids having atendency to form subcooled melts cause a marked penetration increaseunder in-vitro conditions. As can be seen from the dissociationconstants, undecenoic acid and octanoic acid are weaker acids thanglutaric acid monomethyl ester or levulic acid. This was compensated bya higher concentration of the two weaker acids, amounting to 15%, ascompared to the concentration of the two stronger acids. However, it canalso be seen that the dissociation constants are so similar that theabsorption-promoting effect cannot be explained by the dissociationconstants. Example 5 demonstrates that it is possible to increase theabsorption even with an acid which obviously has an only slight effecton the penetration promotion of buprenorphine base, if a neutralsubstance, that is dodecanol, is used which forms sub-cooled melts likelevulic acid or glutaric acid monomethyl ester do. The physical effectof the specified adjuvants is sufficiently proved by the five Examples.

Recrystallization of levulic acid or dodecanol during storage did notoccur in any of the samples, even if the storage temperature amounted to4° C.

What is claimed is:
 1. A method of releasing a pharmaceutical agent foreffecting a topical or systemic effect in a patient from a transdermaltherapeutic system having a layered structure and comprising at leastone substance selected from the group of pharmaceutical agents producinga local or systemic effect and at least one auxiliary agent whichincreases the penetration of said pharmaceutical agents and has amelting point above room temperature, which comprises: a) in a firststep preparing said transdermal therapeutic system by using an auxiliaryagent which has been melted and afterwards allowed to form a subcooledmelt by cooling it down to room temperature, and b) in a second stepapplying the transdermal therapeutic system as prepared in the firststep on the skin of said patient.
 2. The method according to claim 1,wherein the pharmaceutical agent producing a local effect is a memberselected from the group consisting of antiperspirants, fungicides,bactericides, and bacteriostatics.
 3. The method according to claim 1,wherein the pharmaceutical agent producing a systemic effect is a memberselected from the group consisting of antibiotics, hormones,antipyretics, antidiabetic agents, coronary vasodilators, cardioactiveglycosides, analgetics, spasmolytics, antihypertensives, psychotropicdrugs, migraine analgesics, corticoids, contraceptives, antirheumatics,anticholinergics, symphaticolytics, symphaticomimetics, vasodilators,anticoagulants, and antiarrhytmics.
 4. The method according to claim 1,wherein the pharmaceutical agent producing a systemic effect is a memberselected from the group consisting of buprenorphine base, pilocarpinebase, and ephedrine base.
 5. The method according to claim 1, whereinthe pharmaceutical agent is buprenorphine base and the auxiliary agentis selected from the group consisting of levulic acid, glutaric acidmonomethyl ester and dodecanol.
 6. The method according to claim 1,wherein the pharmaceutical agent is buprenorphine base and the auxiliaryagent is levulic acid.